NM_001110792.2:c.953G>C

Variant names:

• chrX-154030911-C-G
• rs61751443
• NM_001110792.2:c.953G>C
• MECP2 p.Arg318Pro

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP5_Strong

The NM_001110792.2(MECP2):c.953G>C (p.Arg318Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R318H: Pathogenic/Likely_pathogenic (ClinVar VariationId 143746, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R318= (synonymous): Likely_benign (ClinVar VariationId 1127365, 1 star)

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.36
• Publications: 34 publications found

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 Gene-Disease associations (from GenCC):

• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, PanelApp Australia
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MECP2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 25 pathogenic, 2 benign (OR vs. background: 51.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R318H: Pathogenic/Likely_pathogenic (ClinVar VariationId 143746, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R318= (synonymous): Likely_benign (ClinVar VariationId 1127365, 1 star)
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MECP2 NM_001110792.2	MANE Select	c.953G>C p.Arg318Pro	missense	Exon 3 of 3	Prot: NP_001104262.1 UniProt:
	MECP2 NM_004992.4	MANE Plus Clinical	c.917G>C p.Arg306Pro	missense	Exon 4 of 4	Prot: NP_004983.1 UniProt:
	MECP2 NM_001316337.2		c.638G>C p.Arg213Pro	missense	Exon 5 of 5	Prot: NP_001303266.1

MECP2 NM_001110792.2

MANE Select

HGVSc / HGVSpc.953G>Cp.Arg318Pro

Exon rankExon 3 of 3

missense

Prot: NP_001104262.1UniProt: A0A140VKC4P51608-2

MECP2 NM_004992.4

MANE Plus Clinical

HGVSc / HGVSpc.917G>Cp.Arg306Pro

Exon rankExon 4 of 4

missense

Prot: NP_004983.1UniProt: D3YJ43P51608-1

MECP2 NM_001316337.2

HGVSc / HGVSpc.638G>Cp.Arg213Pro

Exon rankExon 5 of 5

missense

Prot: NP_001303266.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MECP2 ENST00000453960.7	TSL:1MANE Select	c.953G>C p.Arg318Pro	missense	Exon 3 of 3	Prot: ENSP00000395535.2 UniProt:
	MECP2 ENST00000303391.11	TSL:1MANE Plus Clinical	c.917G>C p.Arg306Pro	missense	Exon 4 of 4	Prot: ENSP00000301948.6 UniProt:
	MECP2 ENST00000630151.3	TSL:5	c.917G>C p.Arg306Pro	missense	Exon 4 of 4	Prot: ENSP00000486089.2 UniProt:

MECP2 ENST00000453960.7

TSL:1MANE Select

HGVSc / HGVSpc.953G>Cp.Arg318Pro

Exon rankExon 3 of 3

missense

Prot: ENSP00000395535.2UniProt: P51608-2

MECP2 ENST00000303391.11

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.917G>Cp.Arg306Pro

Exon rankExon 4 of 4

missense

Prot: ENSP00000301948.6UniProt: P51608-1

MECP2 ENST00000630151.3

TSL:5

HGVSc / HGVSpc.917G>Cp.Arg306Pro

Exon rankExon 4 of 4

missense

Prot: ENSP00000486089.2UniProt: A0A0D9SEX1P51608-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
FATHMM_MKL	Uncertain	0.90	D
FuncVEP CTI	Pathogenic	0.92
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.76	D
Mutation Taster	N/A	13/87	disease causing (ClinVar)
MutationAssessor	Uncertain	2.2	M
PhyloP100	Uncertain	5.4
popEVE	Benign	-3.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.26	T
Varity_R	N/A	0.79
VESM-3B	Benign	-11

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs61751443;

hg19: chrX-153296362;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar